Vitamin D in Disease Prevention and Cure-Part I - India July 2025

Vitamin D in Disease Prevention and Cure-Part I: An Update on Molecular Mechanism and Significance on Human Health
Note: It takes 5,000 IU daily to get half of the people to 40 ng (2,000 gets half to 30 ng)

Vitamin D in Disease Prevention and Cure-Part I: An Update on Molecular Mechanism and Significance on Human Health

Review Indian J Clin Biochem. 2025 Jul;40(3):339-381. doi: 10.1007/s12291-024-01251-7 behind paywall until 7/2026
Shailendra Dwivedi # 1, Vijay Singh # 1, Aniruddha Sen 1, Dharamveer Yadav 2, Ruchika Agrawal 3, Surekha Kishore 4, Sanjeev Misra 5, Praveen Sharma 2

Vitamin D, a versatile secosteroid hormone, continues to captivate scientific interest due to its multifaceted influence on human health. This comprehensive review, part 1 of a series, provides an up-to-date exploration of the molecular mechanisms governing Vitamin D's impact on various aspects of health. Focusing on its pivotal role in the central nervous system (CNS), neurodevelopmental disorders, and neurodegenerative diseases, the review also delves into its intriguing correslations with oral, prostate, breast, and colon cancers. Beyond these domains, Vitamin D's reach extends to viral infections and reproductive health, affecting fertility in both males and females and playing a crucial role throughout pregnancy. The article offers an in-depth examination of the complex molecular pathways and signaling cascades through which Vitamin D exerts its physiological effects. Importantly, it provides a detailed overview of Vitamin D's involvement in a spectrum of diseases, laying the foundation for the upcoming second part of the article. This forthcoming article (part II) will expand on the role of Vitamin D in additional diseases, contributing to a more comprehensive understanding of its therapeutic potential. In summary, this article serves as a valuable resource for researchers and healthcare professionals, offering insights into the diverse roles of Vitamin D and setting the stage for further exploration in part II.

Note: Perplexity is able to review about half of the PDFs that are behind paywalls - July 2025

Summary by Perplexity AI July 2025

Vitamin D in Disease Prevention and Cure-Part I: An Update on Molecular Mechanism and Significance on Human Health
This comprehensive report examines the recent publication by Shailendra Dwivedi and colleagues, published in the Indian Journal of Clinical Biochemistry in July 2024, which provides a detailed analysis of vitamin D's role in disease prevention and cure with particular emphasis on molecular mechanisms and human health significance.

Overview

The publication "Vitamin D in Disease Prevention and Cure-Part I: An Update on Molecular Mechanism and Significance on Human Health" represents the first part of a comprehensive two-part series exploring vitamin D's multifaceted role in human health 1. Published as part of a collaboration between leading researchers from multiple institutions, this work provides an updated exploration of the complex molecular mechanisms through which vitamin D exerts its physiological effects across various disease states 1.
The research team, led by Shailendra Dwivedi, focuses extensively on vitamin D's pivotal role in the central nervous system (CNS), neurodevelopmental disorders, neurodegenerative diseases, and its intriguing correlations with various cancers including oral, prostate, breast, and colon cancers 1. The publication also examines vitamin D's impact on viral infections and reproductive health, affecting fertility in both males and females while playing crucial roles throughout pregnancy 1.

Genomic Actions and Vitamin D Receptor Signaling

Vitamin D's biological activities are primarily mediated through the vitamin D receptor (VDR), a ligand-activated transcription factor belonging to the nuclear receptor superfamily 2. When the active metabolite 1,25-dihydroxyvitamin D₃ (calcitriol) binds to VDR, it forms a heterodimer with the retinoid X receptor (RXR) 3. This VDR/RXR complex then translocates to the nucleus and binds to specific DNA sequences called vitamin D response elements (VDREs) located in the promoter regions of target genes 4 2.
VDREs typically consist of two conserved hexameric half-sites separated by a three-nucleotide spacer, referred to as a DR3 (direct repeat spaced by 3) type element 4. The VDR complex recruits various coregulatory proteins, including coactivators and corepressors, which facilitate or inhibit transcriptional activity 2. These coactivators form bridges between the VDR/RXR complex and the basal transcriptional machinery, including RNA polymerase II, while also recruiting histone acetyltransferases to modify chromatin structure 4.
Current research indicates that vitamin D regulates the expression of thousands of genes through this genomic pathway 5. The complexity of vitamin D signaling has been further revealed through genome-wide analyses, which demonstrate that multiple regulatory regions, often located many kilobases upstream, downstream, or within transcription units themselves, participate in transcriptional modulation 2.

Non-Genomic Mechanisms

Beyond its well-characterized genomic actions, vitamin D also exerts rapid, non-genomic effects that occur within minutes and are independent of protein synthesis 6. These non-genomic actions involve membrane-associated vitamin D receptors, including membrane-associated VDR (mVDR) and protein disulfide isomerase family A member 3 (PDIA3) 5 6.
Non-genomic vitamin D signaling triggers rapid activation of various signaling molecules, including phospholipase C, phospholipase A₂, phosphatidylinositol-3 kinase (PI3K), and p21ras 7. This activation leads to the generation of second messengers such as calcium, cyclic AMP, fatty acids, and 3-phosphoinositides, accompanied by the activation of protein kinases including protein kinase A, src, mitogen-activated protein kinases, protein kinase C, and calcium-calmodulin kinase II 7.
These rapid responses also include the opening of calcium and chloride channels, facilitating calcium influx through L-type voltage-gated calcium channels 7 6. In neuronal tissue, vitamin D's non-genomic actions play crucial roles in calcium regulation, with physiological concentrations of 1,25(OH)₂D₃ leading to rapid calcium influx in specific neuronal populations 8.

Vitamin D in Neural Development and Function

The central nervous system represents one of the most significant extra-skeletal targets of vitamin D action 9. Vitamin D receptors and metabolizing enzymes are widely distributed throughout the brain, including the substantia nigra, hippocampus, hypothalamus, thalamus, and cerebellum 10. The discovery of vitamin D's presence in these regions has led to extensive research into its neuroprotective and neurodevelopmental functions 9.
During brain development, vitamin D deficiency leads to alterations in dopamine neuron specification and positioning 8. Research has shown that developmental vitamin D deficiency results in reduced expression of specification factors crucial for dopamine neurons, altered dopamine turnover, and decreased lateral positioning of dopamine neurons that form the substantia nigra 8. These developmental anomalies can be rescued by maternal treatment with 1,25(OH)₂D₃, highlighting the critical importance of adequate vitamin D levels during pregnancy for proper fetal brain development 8.

Neurotrophic Factor Regulation

Vitamin D significantly influences the expression of neurotrophic factors that are essential for neuronal survival and function 8. Early studies demonstrated that vitamin D promotes the expression of neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and nerve growth factor (NGF) 8. These vitamin D-mediated increases in NGF have been shown to be highly relevant for neuronal survival in vitro 8.
For dopaminergic neurons specifically, vitamin D regulates the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) 8. The hormone suppresses GDNF family receptor alpha 1 (GFRa1) while upregulating the proto-oncogene tyrosine-protein kinase receptor Ret (C-Ret), which is another major receptor for GDNF 8. Blocking vitamin D-mediated increases in GDNF synthesis prevents vitamin D's trophic effects on dopaminergic neurons 8.

Calcium Regulation in Neural Tissue

Vitamin D plays a dual role in neuronal calcium regulation through both genomic and non-genomic mechanisms 8. Chronic vitamin D treatment decreases the expression of Cav1 (an L-type voltage-gated calcium channel subunit), which reduces calcium influx in response to reactive oxygen species, inflammation, or stress 8. This genomic action helps prevent calcium-mediated toxicity in neurons 8.
Conversely, the rapid non-genomic actions of vitamin D increase calcium influx in cortical neurons through L-type voltage-gated calcium channels 8. This rapid calcium influx is essential for normal neuronal function and neurotransmission 8. The balance between these opposing effects allows vitamin D to maintain optimal calcium homeostasis in neural tissue 8.

Alzheimer's Disease

Alzheimer's disease (AD) represents one of the leading causes of dementia worldwide, characterized by progressive cognitive decline and memory loss 11. The relationship between vitamin D deficiency and AD has been extensively studied, with multiple lines of evidence suggesting a protective role for adequate vitamin D levels 11 12.
Low vitamin D levels have been consistently associated with impaired cognitive function and increased risk of developing AD 11 1. Meta-analyses have demonstrated that vitamin D deficiency significantly increases the risk of dementia and Alzheimer's disease 11. The mechanisms underlying vitamin D's neuroprotective effects in AD include its ability to reduce amyloid-beta (Aβ)-associated neurodegeneration, modulate inflammatory responses, and support neuronal calcium homeostasis 11.
Research has shown that vitamin D supplementation may improve cognitive functions in AD patients 11. One study reported that combined treatment with memantine and vitamin D improved cognitive function in AD patients, providing significant therapeutic effects in disease prevention 11. Additionally, vitamin D has been found to stimulate IL-34 production, which constitutes an important mechanism in vitamin D's protective activity against AD 11 .

Parkinson's Disease

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra 11 12. Given vitamin D's crucial role in dopaminergic neuron development and function, vitamin D deficiency has been implicated in PD pathogenesis 11 8.
Studies have consistently found higher prevalence of vitamin D deficiency in Parkinson's cohorts compared to healthy controls 11 11 The neuroprotective effects of vitamin D in PD may be mediated through several mechanisms, including antioxidative system activation, calcium regulation, immunomodulation, enhanced neurotransmission, and detoxification 11 . Chronic vitamin D deficiency is predicted to cause dopaminergic neuron loss in the substantia nigra region, potentially leading to Parkinson's disease in later stages 11 .
Experimental studies have demonstrated that vitamin D treatment reduces pro-inflammatory cytokines while upregulating anti-inflammatory cytokines, providing neuroprotective effects in PD models 11 . Additionally, vitamin D-activating enzyme CYP27B1 has been identified in specific astrocyte subpopulations in PD, where these cells may display neuroprotective properties by sequestering α-synuclein oligomers 11 .

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system that has shown strong associations with vitamin D status 13 12. Epidemiological evidence demonstrates geographical and seasonal correlations between vitamin D exposure and MS risk and disease activity 13. Higher latitudes, which receive less sunlight exposure, show increased MS prevalence 13.
Vitamin D's protective effects in MS are primarily attributed to its immunomodulatory properties 13 12. The hormone modulates both innate and adaptive immune responses, suppressing inflammatory T helper (Th)1 and Th17 cells while promoting immunotolerogenic T regulatory responses 14. In experimental autoimmune encephalomyelitis (EAE), the animal model of MS, vitamin D has been shown to have both prophylactic and therapeutic effects 13.
Research indicates that vitamin D supplementation may reduce oxidative stress in MS patients, with various doses showing beneficial effects on oxidative stress in relapsing-remitting MS 11 . Four Mendelian randomization studies have found increased risk of multiple sclerosis in individuals with genetically lowered serum 25(OH)D concentrations, suggesting a causal relationship between vitamin D deficiency and MS risk 15.

Colorectal Cancer

The relationship between vitamin D and colorectal cancer represents one of the most consistently documented associations in cancer research 16 17. Observational studies have revealed consistent inverse associations between vitamin D status and colorectal cancer incidence and mortality 16. Higher serum 25-hydroxyvitamin D levels are associated with reduced risk of developing colorectal cancer and improved survival outcomes 16 17.
Mechanistically, vitamin D's anti-cancer effects in colorectal tissue involve multiple pathways 18. The hormone regulates Wnt signaling, which is crucial for maintaining appropriate stem cell differentiation along the crypt-villus axis 18. Vitamin D also modulates inflammation in the gut, which is a known risk factor for colorectal carcinogenesis 18. In animal models, vitamin D analogs inhibit proliferation, colitis, and the development of aberrant crypt foci, which are pre-neoplastic lesions that predispose to colon tumorigenesis 18.
The vitamin D receptor (VDR) is highly expressed in normal colonic epithelial cells, and VDR knockout mice show increased susceptibility to intestinal inflammation and tumorigenesis 18. Dietary supplementation with vitamin D₃ and 25(OH)D reduces colon tumor incidence by approximately 50% in animal models without adverse effects 18.

Breast Cancer

The evidence for vitamin D's role in breast cancer prevention shows mixed results, with observational studies generally demonstrating relationships between higher 25(OH)D levels and lower risk for disease progression and mortality 16. However, randomized clinical trials have generally failed to support these observational findings 16 17.
Vitamin D's anti-tumor effects in breast tissue involve modulation of tissue responsiveness to estrogen, a known driver of breast cancer 18. The hormone influences cell proliferation, differentiation, and survival pathways that are crucial for maintaining normal breast epithelial cell function 18. Pre-clinical studies in animal models have demonstrated that dietary vitamin D supplementation decreases tumor development in breast tissue 18.
The vitamin D receptor is highly expressed in breast epithelial cells, providing a direct molecular link for vitamin D's effects on breast tissue homeostasis 18. However, sensitivity to vitamin D often becomes reduced as cancer progresses due to decreased expression or activity of VDR and vitamin D metabolizing enzymes 18.

Prostate Cancer

The relationship between vitamin D and prostate cancer presents a complex and somewhat paradoxical picture compared to other cancer types 16 19. Approximately 30 studies have investigated the association between 25(OH)D and prostate cancer incidence, with only two reporting clear inverse relationships 16. In fact, several studies have demonstrated increased prostate cancer risk associated with higher vitamin D concentrations 16 19.
A 2014 meta-analysis of 21 studies reported that higher 25(OH)D concentrations were associated with higher risk for developing prostate cancer 16. This finding has been supported by Mendelian randomization analyses, which showed direct associations between genetic variants predicting higher vitamin D levels and aggressive prostate cancer risk 19.
Despite the concerning associations with cancer incidence, some evidence suggests vitamin D may help prevent progression of early-stage prostate cancer 16. One open-label clinical trial suggested that supplementation with 4,000 IU/day of vitamin D₃ may inhibit disease progression 16. The mechanisms underlying these complex relationships remain under investigation 16 19.

Innate Immunity

Vitamin D plays crucial roles in regulating both innate and adaptive immune responses 14 20. The discovery that antigen-presenting cells such as macrophages and dendritic cells can actively metabolize 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D provided the foundation for understanding vitamin D's immune functions 14. These cells also express the vitamin D receptor, enabling local vitamin D signaling within immune tissues 14.
At the innate immunity level, vitamin D stimulates the expression of antimicrobial peptides, particularly cathelicidin (LL-37) and defensin 2 14. These antimicrobial peptides provide broad-spectrum protection against bacteria, viruses, and fungi 14. The induction of cathelicidin by vitamin D is robust across multiple cell types and has been confirmed in both in vitro and in vivo studies 14.
Vitamin D also enhances autophagy, a cellular process crucial for combating intracellular pathogens such as Mycobacterium tuberculosis and viral infections 14 20. By potently enhancing autophagy, vitamin D helps clear intracellular pathogens and supports cellular defense mechanisms 14. Additionally, vitamin D lowers intracellular iron concentrations via suppression of hepcidin, creating an environment less favorable for pathogen growth 14.

Adaptive Immunity

In the adaptive immune system, vitamin D modulates T cell responses through direct effects on T cell activation and indirect effects on antigen-presenting cells 14 20. The hormone suppresses inflammatory T helper (Th)1 and Th17 cell responses while promoting immunotolerogenic T regulatory (Treg) cell development 14. This shift toward a more tolerogenic immune profile helps prevent excessive inflammatory responses and autoimmune reactions 14.
Vitamin D influences dendritic cell function, promoting their development into tolerogenic antigen-presenting cells 14. These tolerogenic dendritic cells are less likely to activate aggressive T cell responses and more likely to promote immune tolerance 14. The local synthesis of 1,25(OH)₂D by macrophages and dendritic cells appears to play a pivotal role in mediating these T cell responses 14.
Recent genome-wide analyses have revealed that cytokine signaling pathways can influence the intracrine vitamin D system, either enhancing or abrogating cellular responses to vitamin D 21. This finding highlights the complex interplay between vitamin D signaling and other immune regulatory pathways 21.

Male Fertility

Vitamin D's role in male reproductive health has gained significant research attention, with vitamin D receptors identified in various components of the male reproductive system 22 23. VDR has been discovered in the smooth muscles of the epididymis, spermatogonia, and Sertoli cells of male rodents, indicating important roles in spermatogenesis and sperm maturation 22.
Animal studies have provided compelling evidence for vitamin D's importance in male fertility 22. Male rats fed vitamin D-deficient diets showed 45-55% decreased successful mating rates compared to animals fed vitamin D-rich diets 22. The fertility of normal female rats inseminated by vitamin D-deficient males was reduced by 73% 22. These vitamin D-deficient males exhibited lower testicular and epididymal sperm counts, Sertoli cell dysfunction, fewer Leydig cells, and degenerative changes in reproductive epithelium 22.
VDR knockout mouse models have provided similar findings, with male mice showing lower sperm count and motility, as well as testicular histological abnormalities including dilated seminiferous tubule lumens, thinner epithelial cell layers, and decreased spermatogenesis 22. These findings strongly support vitamin D's essential role in testicular function and male fertility 22.

Female Fertility and Pregnancy

Vitamin D receptors are found throughout female reproductive tissues, including the ovary, uterus, and endometrium, suggesting important roles in female reproduction 23 24. Calcitriol, the active form of vitamin D, effectively controls the secretion of human placental lactogen, estrogen, and progesterone 25. In vitro studies have shown that 1α,25-dihydroxy vitamin D₃ improves ovarian follicle survival and growth 25.
During pregnancy, vitamin D requirements increase significantly 24. Serum levels of 1,25-hydroxyvitamin D increase up to two-fold starting at 10-12 weeks of gestation and reach maximum levels in the third trimester 26. The placenta plays a key role in transporting vitamin D to the fetus, which is totally dependent on the mother's vitamin D status 26.
Vitamin D deficiency during pregnancy has been associated with increased risks of preeclampsia, altered immune responses, and preterm birth 26 24. Additionally, vitamin D deficiency in mothers is linked to vitamin D deficiency in infants, with prevalence ranging from 28% to 90% 26. In India, the prevalence of hypovitaminosis D ranges from 42% to 74% among pregnant women and 44.3% to 66.7% among infants 26.
Research indicates that maintaining serum 25(OH)D levels above 30 ng/mL before pregnancy and during the first trimester, with sufficient levels maintained throughout pregnancy, provides significant protective effects 24. However, meta-analyses of human studies have shown mixed results, with some studies demonstrating improved IVF success rates in women with higher vitamin D levels, while others show minimal impact on fertility outcomes 23.

Worldwide Statistics

Vitamin D deficiency represents a significant global health challenge, affecting populations across all regions and demographics 27 28 29. A comprehensive analysis of 7.9 million participants from 81 countries revealed alarming deficiency rates: 15.7% of individuals had serum 25-hydroxyvitamin D levels below 30 nmol/L (severe deficiency), 47.9% had levels below 50 nmol/L (deficiency), and 76.6% had levels below 75 nmol/L (insufficiency) 27 29.
The prevalence of vitamin D deficiency varies significantly by geographic region 27 29. The Eastern Mediterranean region shows the highest prevalence, with some countries like Kuwait showing 58.9% of the population aged 10 and older having severe deficiency 29. In contrast, the Region of the Americas has the lowest prevalence, with only 3.0% of Americans aged 2 and older suffering from severe deficiency 29.
Europe shows intermediate prevalence rates, with 13% of the population having severe deficiency and 40% having levels below 50 nmol/L 28 29. The prevalence is higher during winter months (17.7%) compared to summer (8.3%) 27. In South Asia, vitamin D deficiency is particularly problematic, with overall rates of 68% and the highest rates observed in Pakistan (73%), followed by Bangladesh (67%) and India (67%) 27.

Risk Factors and Demographics

Several factors contribute to the high global prevalence of vitamin D deficiency 27 29. Latitude plays a crucial role, with people living at higher latitudes showing increased deficiency rates due to reduced ultraviolet B radiation exposure 29. Seasonal variations are significant, with winter-spring prevalence being 1.7 times higher than summer-autumn rates 29.
Gender differences are notable, with females consistently showing higher vulnerability to vitamin D deficiency across multiple regions 27 29. This gender disparity may be related to cultural practices in some regions, such as wearing veils or limited sun exposure, dietary differences, or physiological factors related to pregnancy and lactation 29.
In certain populations, vitamin D deficiency reaches extremely high levels 28. Patients with chronic renal failure and those on hemodialysis, renal transplant recipients, and individuals with liver disease may have deficiency prevalence ranging from 85% to 99% 28. Low- and middle-income countries face particular challenges, with deficiency prevalence often exceeding 20% due to inadequate dietary intake and limited sunlight exposure 27.

Official Guidelines

The 2024 Endocrine Society Clinical Practice Guideline represents the most recent comprehensive approach to vitamin D supplementation and testing 30 31. These updated guidelines, which replace previous 2011 recommendations, have simplified the approach to vitamin D assessment and supplementation 31. Notably, the new guidelines no longer categorize vitamin D status in terms of "deficiency" and "insufficiency" based on specific serum 25(OH)D levels 31.
For most adults aged 19 to 74, the guideline advises against routine vitamin D testing or supplementation 31. Instead, it recommends following the U.S. National Academy of Medicine's daily intake guidelines: 600 IU until age 70 and 800 IU daily for those over 70 30 31. However, for adults aged 75 and older, empirical vitamin D supplementation is recommended due to potential mortality benefits, focusing on low daily doses of approximately 1,000 IU 31.
The guidelines include special recommendations for specific populations 31. Pregnant women are advised to take vitamin D through fortified foods or supplements to ensure sufficient intake 31. Adults with high-risk prediabetes should receive vitamin D supplementation, as research suggests it may help lower the risk of progressing to type 2 diabetes 31.

Alternative Recommendations (40+ ng, 2000+ IU daily)

Despite official conservative recommendations, many researchers advocate for higher vitamin D intake levels 32 33. Evidence suggests that achieving serum 25(OH)D concentrations above 40 ng/mL (100 nmol/L) may be optimal for disease prevention and reducing morbidities and mortality 34 35. To achieve these levels, daily supplementation with 2,000-4,000 IU (50-100 μg) may be necessary for many individuals 32 33.
The rationale for higher doses is based on individual participant data meta-analyses showing that conventional doses of 600-800 IU may not be sufficient to achieve target concentrations of at least 50 nmol/L in many individuals 33. Factors such as obesity, malabsorption syndromes, or medications that impair vitamin D metabolism require higher doses 33. For dark-skinned individuals residing at higher latitudes, vitamin D requirements may be particularly elevated, with some studies suggesting needs of 2,000-2,700 IU daily to achieve adequate levels 33.
A daily vitamin D supplement dose of 2,000 IU (50 μg) has been proposed as a reasonable one-size-fits-all approach for preventing and treating vitamin D deficiency in the general adult population 33. This recommendation is supported by the demonstrated safety of this dose over several years of treatment and evidence supporting clinical extraskeletal benefits at this level 33.

Advanced Molecular Understanding

Recent advances in molecular biology have significantly expanded our understanding of vitamin D's mechanisms of action 2 36. Genome-wide analyses using chromatin immunoprecipitation techniques combined with various gene scanning methodologies have revealed new insights into the location, structure, and function of vitamin D regulatory regions 2. These studies demonstrate that vitamin D enhancers are often located many kilobases away from target genes and can function in complex modular patterns 2.
The discovery that vitamin D influences epigenetic modifications has opened new avenues for understanding its long-term effects on gene expression 37. Vitamin D treatment affects chromatin accessibility, with some chromatin loci opening within 2 hours of ligand stimulation while others require 24 hours to reach maximal accessibility 37. This temporal pattern suggests that many vitamin D effects on the epigenome are secondary, mediated by genes and proteins that are primary vitamin D targets 37.
Recent research has also highlighted the importance of pioneer transcription factors in vitamin D signaling 37. Factors such as PU.1, CEBPα, GABPα, ETS1, RUNX2, and BACH2 may take first contact with enhancer regions, optimizing access for VDR binding and facilitating chromatin modifications 37. This discovery has revealed vitamin D signaling to be more complex than previously appreciated, involving dynamic protein complexes that change over time 37.

Metabolomics and Personalized Medicine

Emerging fields such as metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D supplementation 34 35. These approaches may help identify individuals who would benefit most from vitamin D supplementation and determine optimal dosing strategies based on genetic and metabolic profiles 34.
Research into vitamin D-binding protein (DBP) and bioavailable vitamin D has revealed additional complexity in vitamin D physiology 38. Approximately 85-90% of total 25(OH)D is bound to DBP, 10-15% is loosely bound to albumin, and less than 1% circulates in free form 38. Some researchers suggest that bioavailable or free 25(OH)D may better reflect vitamin D status and its associations with health outcomes than total 25(OH)D levels 38.
The concept of precision medicine in vitamin D supplementation is gaining traction, with researchers proposing individualized dosing based on factors such as body weight, baseline vitamin D status, genetic polymorphisms in vitamin D metabolizing enzymes and receptors, and specific health conditions 34 33. This approach recognizes that vitamin D requirements vary considerably between individuals and populations 33.

Disease-Specific Considerations (when more Vitamin D is needed)

The mounting evidence for vitamin D's role in various diseases has important implications for clinical practice 34. For neurological conditions, maintaining adequate vitamin D levels may be particularly important for disease prevention and progression 11 12. Patients with multiple sclerosis, Parkinson's disease, and Alzheimer's disease should be screened for vitamin D deficiency and supplemented accordingly 12.
In cancer prevention, the evidence is strongest for colorectal cancer, where maintaining higher vitamin D levels appears protective 16 17. However, the complex relationship with prostate cancer requires careful consideration, as higher vitamin D levels may actually increase risk in some populations 16 19. These findings highlight the need for individualized approaches to vitamin D supplementation in cancer prevention 19.
For immune function, vitamin D supplementation may be particularly beneficial during infectious disease outbreaks or in immunocompromised populations 14 20. The COVID-19 pandemic has renewed interest in vitamin D's immune-modulatory effects, with some studies suggesting benefits for infection prevention and severity reduction 39.

Safety and Monitoring

While vitamin D supplementation is generally safe, high doses can lead to toxicity 40. Symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, and in severe cases, kidney stones and renal failure 40. The upper limit for safe long-term supplementation is generally considered to be 4,000 IU (100 μg) daily for adults, though some individuals may tolerate higher doses 40 33.
Regular monitoring of serum 25(OH)D levels may be warranted in individuals taking higher-dose supplements or those at risk for deficiency 40. Target levels for optimal health remain debated, but most experts agree that levels below 20 ng/mL (50 nmol/L) should be avoided, while levels above 30 ng/mL (75 nmol/L) may be optimal for extra-skeletal health benefits 34 35.

Conclusion

The publication by Shailendra Dwivedi and colleagues represents a significant contribution to our understanding of vitamin D's complex roles in human health and disease prevention 1. Their comprehensive analysis of molecular mechanisms reveals vitamin D to be far more than a simple vitamin, functioning instead as a pleiotropic hormone with effects on virtually every organ system 1.
The evidence reviewed demonstrates vitamin D's crucial roles in central nervous system function, immune regulation, cancer prevention, reproductive health, and numerous other physiological processes 1. The molecular mechanisms underlying these effects involve both genomic actions through the vitamin D receptor and rapid non-genomic responses through membrane-associated receptors 1.
Despite decades of research, significant gaps remain in our understanding of optimal vitamin D levels, appropriate supplementation strategies, and the mechanisms underlying tissue-specific responses to vitamin D 1. The high global prevalence of vitamin D deficiency represents a major public health challenge that requires coordinated efforts from healthcare providers, policymakers, and public health officials 27 29.
Future research should focus on personalized approaches to vitamin D supplementation, better understanding of the complex relationships between vitamin D and various diseases, and development of evidence-based guidelines that consider individual risk factors and health status 1 34. The forthcoming second part of Dwivedi and colleagues' series will undoubtedly provide additional insights into vitamin D's therapeutic potential across an even broader range of diseases 1.
As our understanding of vitamin D's molecular mechanisms continues to evolve, it becomes increasingly clear that maintaining adequate vitamin D status is essential for optimal health across the lifespan 1 34. The integration of vitamin D assessment and supplementation into routine clinical practice, guided by evidence-based recommendations and individualized risk assessment, represents a promising approach for improving public health outcomes and reducing the burden of chronic diseases 1 34.
References

Note: It takes 5,000 IU daily to get half of the people to 40 ng (2,000 gets half to 30 ng)

Dose Response Dec 2015 (VDW# 7156)
chart is the summary of 36 dose-response studies